One of the strategies being considered for the prevention of cancer is to inhibit the carcinogenic process by the administration of chemopreventive agents. The flavonoids are a group of compounds which have been widely studied in this regard. These compounds are known to both inhibit and stimulate carcinogen metabolism by the cytochrome P-450 monooxygenase system as well as to alter the occurrences of the P-450 isozymes. Since this enzyme system catalyzes both activation and detoxication pathways of carcinogen metabolism, one mode of action of the flavonoids and other inhibitors of carcinogenesis may be to alter the balance between activation and detoxication pathways in a manner which diminishes the extent of activation. Recent evidence suggests that the flavonoids as well as various steroids may modulate the activities of individual forms of cytochrome P-450 in a substrate specific manner, and that these compounds may function as allosteric effectors. The projects in this application will extend these observations to a greater number of substrates and develop structure/activity relationships governing the actions of the modulating agents. In addition, we will examine the underlying mechanisms by which this modulation occurs. These results will be contrasted to the activity of the flavonoids as inducers of specific forms of P-450. The impact of the modulation and induction of specific forms of P-450 on the metabolism of aflatoxin B1 and 2-acetylaminofluorene in isolated rabbit hepatocyte cultures will then be assessed. It is anticipated that the results of these studies will aid in the design of efficacious chemopreventive agents for the inhibition of carcinogenesis.